Components of tobacco smoke, primarily organic nitrites, nitrous oxide, cyanates and cyanides are known to attack some forms of B12 and folate coenzymes transforming them into biologically inactive compounds. We propose to investigate the hypothesis that, via this mechanism, exposure to cigarette smoke results in a localized B12 and folate deficiency limited primarily to the bronchial epithelium which renders it more susceptible to neoplastic transformation by the carcinogenic hydrocarbons of tobacco smoke. Substantial evidence, reviewed in the body of the application, supports the notion that folate deficient cells are more susceptible to neoplastic transformation. Furthermore, work from our laboratory has indicated that folate supplementation in humans can prevent, and even reverse, the progression of pre-neoplastic lesions of cervical dysplasia. We postulate that in the B12: folate deficient cells available folates are shifted away from the pathways of nucleotide biosynthesis resulting in an inadequate supply of nucleotides, (primarily thymidylate) whicih: a) impairs DNA repair, and b) prolongs mitosis accumulating cells at a stage of their life cycle when the DNA may be more susceptible to carcinogen attack. Specifically we propose to: 1) investigate the presence of megaloblastic changes indicative of B12-folate deficiency in the bronchial epithelium of smokers; 2) study the effects of components of tobacco smoke upon B12 and folate coenzymes in vitro; 3) attempt to demonstrate that the levels of B12 and folates and the activities of key B12 and folate-requiring enzymes in the bronchial epithelium of smokers are lower than in normals and 4) investigate the effects upon the progression of dysplastic lesions of the bronchial epithelium of chronic smokers, of B12 and folate supplementation. The possibility of prevention of lung cancer by impeding or reversing the progession of pre-neoplastic lesions via an adequate supply of B12 and folate to the exposed epithelia is envisioned.
| Heimburger, D C (1992) Localized deficiencies of folic acid in aerodigestive tissues. Ann N Y Acad Sci 669:87-95;discussion 95-6 |
| Heimburger, D C; Alexander, C B; Birch, R et al. (1988) Improvement in bronchial squamous metaplasia in smokers treated with folate and vitamin B12. Report of a preliminary randomized, double-blind intervention trial. JAMA 259:1525-30 |
| Heimburger, D C (1987) Diet, diet supplements, and cancer. Ala J Med Sci 24:442-6 |
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| Butterworth Jr, C E (1985) Vitamin deficiency and cancer. Med Oncol Tumor Pharmacother 2:165-74 |
